Denham Harman and the History of the Free Radical Theory of Aging
Select Proceedings of the 2nd Annual Monaco Anti-Aging Conference
By
Denham Harman, PhD, MD [Edited by Ward Dean, MD]
Introduction: Today, the words free radicals are virtually a household name—and free radical scavengers, or antioxidants, crowd the shelves of health food stores and pharmacies alike. Yet nearly five decades ago, one man had the realization and determination to pursue his research and bring to the attention of the world the existence, formation, and damaging effects of free radicals. Here to explain his free radical theory of aging, it is an honor and a privilege to introduce to you, Dr. Denham Harman.
First, I would like to thank Rob Watson and the other members of the organizing committee for inviting me to participate in this conference in this magnificent location to talk on The Free Radical Theory of Aging. I am going to say a few words about the phenomenon of aging, the origin of the Free Radical Theory of Aging, and some of its applications including the pathogenesis of disease.
How I Became Interested in the Aging Process
I began my professional career working for nearly 15 years in the chemistry laboratories of Shell Development Company, a research arm of Shell Oil. During that period I received my BS and PhD degrees from the College of Chemistry at UC Berkeley. As an undergraduate I majored in chemistry and physics, and minored in mathematics. When I finished my BS degree, I went to work for an organic chemist who gave me a fair amount of opportunity to do organic syntheses. When I completed my PhD degree in organic chemistry, I switched to the Reaction Kinetics Department at Shell. Most of the work at Shell was done on free radical chemistry. During my six and a half years in that department I received 35 United States patents in various aspects of chemistry of free radicals. Also, I developed an interest in biology.
During that time, my interest in biology was further increased one night when I came home from work in the first part of December. My wife called attention to an article in a popular magazine that she thought I might find of interest. I did. The article, titled, Tomorrow You May Be Younger, was written by William Lawrence, Science Editor of the New York Times. In large part, that is the reason I am talking to you today. Without my wife showing me that article, I think I would be doing something else at this point. [Mrs. Harman stands in response to an ovation from the audience].
I then spent four years at Stanford Medical School and did a rotating internship at the San Francisco City and County Hospital in San Francisco. In July of 1954 I joined the Donner Laboratory of Medical Physics at the University of California at Berkeley as a research associate of Dr. John Lawrence, a physician. He was the brother of Ernest Lawrence, the man who won the Nobel Prize for his work on the cyclotron. My only definite obligation to the laboratory was to work in the hematology clinics on Wednesday mornings. Other than that, I could do as I pleased. I settled down to the problem of what causes aging and what can we do about it.
Genesis of the Free Radical Theory
I looked at the problem of aging with the premise that there was a basic common cause which could be modified by genetics and the environment. I rapidly became frustrated. I could not account for any one thing that could account for the aging phenomenon that I was acquainted with. The problem became progressively worse and reached the point where I thought, Well, maybe we didn’t know enough about basic knowledge at that point to make it possible to discern what caused aging.
One morning in early November I was sitting at my desk reading, and a phrase—free radicals—crossed my mind. I finally found what I had been looking for. I didn’t say Eureka!, but I felt a profound sense of relief at having found something that made sense, both biologically and chemically. The next month, in December, I walked around the campus at UC Berkeley and spoke with a number of people about the possibility that aging could be caused by free radical reactions. The reaction generally was that it was a nice idea, but it was too simple to account for aging. Only two people thought that the idea might have some merit, and they were both organic chemists. It soon became very obvious that the theory would have to be reduced to practice before anybody would pay any attention to it. So almost simultaneously, we started working in four different areas: one on catalase (and, by analogy, to Fenton’s reagent, which involved free radicals); another on life span studies; another on cancer; and a fourth one on atherosclerosis.
During my time at Donner Laboratory, the first two years were full-time and the second two years were part-time while I completed my residency requirements for Internal Medicine. I published eight papers in those four years. My first paper on the free radical theory, in particular, received a great deal of publicity.1 By the time we left Berkeley to move to Omaha, Nebraska, where I assumed the chair of cardiovascular research, the Free Radical Theory was fairly well known.
The Free Radical Theory of Aging
The Free Radical Theory is that free radical reactions are involved in aging. There are two major aspects to it. One, is that you can decrease the rate of free radical reaction by decreasing the rate of initiation of the chemical reaction; and/or two, you can slow the decrease in the propagation phase. With antioxidants, it might be possible to increase the lifespan.
Figure 1 is representative of many studies.2 It shows a semi-log plot of the chance of death versus age in months of male LEF1 mice. It compared control mice with those given mercaptoethylamine (MEA) in the diet. Nothing else was done. They were started on the diet right after weaning at about three weeks. The researchers found that the MEA resulted in about a 30 percent increase in average life expectancy.
Growing Acceptance for the Free Radical Theory
By the mid-1960s, enough work had been done, based on The Free Radical Theory of Aging, to indicate that it was relatively easy to increase average life expectancy at birth in mice, but no certain increases were observed in maximum lifespan. So the question at that time was—is the theory correct?
Several years later, in 1972, we published a short paper in the Journal of the American Geriatric Society—The Biologic Clock: Mitochondria?—which asserted that the mitochondria were responsible for our lifespan.3 I tried at that time to get other people interested in this possibility. I didn’t have any more luck with that than I had previously in trying to get people interested in the Free Radical Theory of Aging.
In 1978, I stopped by Dr. Jaime Miquel’s laboratory at NASA in California on my way to a medical meeting. Several years later, Dr. Miquel’s team published a couple of papers on mitochondria and aging.4,5 These papers emphasized potential changes in mitochondrial DNA. Not much happened for a number of years after that. I had to wait for growth in the mitochondrial field. In 1989, A.W. Linnane and his group in Melbourne published a paper at last on mitochondria and aging, and that got wide publicity.6 Since then, there has been a growing interest in free radicals and mitochondrial changes in aging.
Gradually, free radical reactions were implicated in a growing number of specific diseases, including the two major causes of death—atherosclerosis and cancer—and many more diseases (Table I).7 Additionally, many studies have shown mutations in most cases are responsible for cancer. If you use antioxidants, you might cut down the rate of mutations and decrease the cancer.
Research Reveals Antioxidant Benefit from Vitamin E
In 1988 researchers in Germany gathered blood samples from about 5,000 women. The samples were put aside for a number of years and then they tabulated the number of breast cancers that developed among the women. They also measured serum levels of vitamin E. Women whose serum vitamin E levels were low at the time the study was started had a high incidence of breast cancer—and those who did not develop breast cancer had higher concentrations of vitamin E. So, low levels of vitamin E appear to predispose women to breast cancer.8
In 1983, two epidemiological studies were published in the American Journal of Medicine — one for males and one for females. They both showed that if individuals took 100 mg or more of vitamin E per day for at least two years, they had a 40% decrease in the incidence of cardiovascular disease.
Future of Medicine—Slowing the Aging Process
I wanted to take a couple of minutes to talk about the aging process, because this is the future of medicine. The aging process is what we are going to have to do something about. One way to slow down the rate of aging is to eat less (caloric restriction)—because when you cut down your food intake, you decrease the rate of oxygen utilization, which decreases the rate of superoxide radical production by the mitochondria, which results in animals living longer. We would live longer, too.
The only problem is that at the same time you decrease your caloric intake, you reduce the production of ATP—a high energy molecule—and you become fatigued. If you cut your caloric intake too far down, you become hungry—and miserable. So I think caloric restriction has limited application.
Spin Traps—Breakthrough in Anti-Aging Therapy
About ten years ago, the prestigious National Academy of Sciences published an article in which the workers studied the effect of phenyl butyl nitrone (PBN) on gerbils.9 PBN is related to a naturally occurring class of antioxidants known as nitrones. Nitrones are the oxidation products of secondary amines containing alpha hydrogens. A nitrone results when oxygen links with nitrogen in the amine. This allows a double bond to form between carbon and nitrogen, giving PBN and other nitrones unique reactive properties. PBN unites with free radicals that bond with the electron-deficient carbon, forming a less reactive radical that can then be excreted before the chain reaction grows.
The scientists used two groups of gerbils—one young, and one old. Before they started their experiment they ran them through a maze test and evaluated the number of errors made by both groups. Figure 2 shows that the old gerbils made over twice as many errors as young animals. However, when they gave these animals injections of phenyl butyl nitrone, after about two weeks the old animals all started acting like young animals.
Substances of this nature are now being studied intensively, and we may see some data in the literature before long, indicating that we might be able to significantly slow down the aging process.
Summary
I have talked a little bit about the phenomenon of aging, the history of The Free Radical Theory of Aging, and the basis by which free radicals cause aging. Also, we reviewed some of the applications of this theory to aging intervention (Table 2). I can’t predict the future, but based on the studies supporting this theory, I believe the chances of being able to interfere with the intrinsic aging process and increase our healthy lifespan are very good.10,11,12
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